The present invention relates to functionalizing carbohydrate derivatives by base-induced .beta.-elimination and subsequent olefination to form products containing a subunit having at least one hydroxyl group and a diene group. More specifically, the present invention relates to functionalizing derivatives of 2-deoxyfuranoses and derivatives of 2-deoxypyranoses by base-induced .beta.-elimination and subsequent olefination to form biologically active derivatives of fatty acids containing .alpha.-hydroxy-diene groups and .alpha.,.beta.-dihydroxy-diene groups, respectively.
The oxidative metabolism of arachidonic acid yields a variety of biologically active substances which are thought to serve as mediators of intracellular events within tissue (Samuelsson, B., et al. (1978) Annu. Rev. Biochem. 42: 997; Lewis, R. A., et al. (1982) Int. J. Immunopharmacol. 4: 85). Action by the cyclooxygenase enzyme leads to the production of prostaglandins (Lands, W. E. M., et al. (1983) Prostaglandins and Related Substances (Pace-Asciak, C., and Granstrom, E., eds) pp. 203-222, Elsevier Scientific Publishing Co., Amsterdam), prostacyclin (Moncado, S., et al. (1987) Thromb. Res. 11: 323), and thromboxanes (Hamberg, M., et al. (1973) Proc. Natl. Acad. Sci. U.S.A. 70: 899), while action by the 5-lipoxygenase enzyme leads to the production of leukotriene A.sub.4 which is the precursor for the sulfidopeptide leukotrienes (slow reacting substance of anaphylaxis) (Murphy, R. C., et al. (1979) Proc. Natl. Acad. Sci. U.S.A. 76: 4275) as well as the chemotactic factor for neutrophils, leukotriene B.sub.4 (Borgeat, P., et al. (1979 ) J. Biol. Chem. 254: 7865). In addition, there are other lipoxygenases which catalyze the production of 12(S)-hydroxyeicosatetraenoic acid (Nugteren, D. H. (1975) Biochim. Biophys. Acta 380: 299) and 15(S)-hydroxyeicosatetraenoic acid (Narumiya, S., et al. (1981) J. Biol. Chem. 256: 9583). Arachidonic acid could also serve as a substrate for hepatic cytochrome P-450 in the generation of hydroxy and epoxy metabolites of this polyunsaturated fatty acid (Capdevila, J., et al. (1981) Proc. Natl. Acad. Sci. U.S.A. 78: 5362; Oliw, E. H., et al. (1982) J. Biol. Chem. 257: 3771; Morrison, A., et al. (1981) Proc. Natl. Acad. Sci. U.S.A. 78: 7375). These molecules, in particular the epoxyeicosatrienoic acids, have potent pharmacological actions releasing peptide hormones such as luteinizing hormone (Snyder, G. D., et al. (1983) Proc. Natl. Acad. Sci. U.S.A. 80: 3504), prolactin (Cashman, J. R., et al. (1987) Neuroendocrinology 46: 246), and somatostatin (Capdevila, J., et al. (1983) Endocrinology 113: 421) from brain tissue, as well as insulin from pancreatic islet cells (Falck, J. R., et al. (1983) Biochem. Biophys. Res. Commun. 114: 743). Furthermore, the cytochrome P-450-derived epoxides have significant effects on the inhibition of chloride transport (Jacobson, H. R., et al. (1984) Prostaglandins and Membrane Ion Transport (Braquet, P., et al. eds) pp. 311-318, Raven Press, New York), inhibition of platelet aggregation (Fitzpatrick, F. A., et al. (1986) J. Biol. Chem. 261: 15334), the ability to mobilize microsomal calcium ions (Kutsky, P., et al. (1983) Prostaglandins 26: 13), and have the property to inhibit calcium ionophore-induced neutrophil aggregation (Kraemer, R., et al. (1987) Am. J. Pathol. 128: 446). It was described that the 12(R)-hydroxyeicosatetraenoic acid (12(R)-HETE), produced by cytochrome P-450 from the bovine corneal epithelial cells, was a potent inhibitor of the Na.sup.+ /K.sup.+ -ATPase in the cornea (Schwartzman, M. L., et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84: 8125).
Recently, it was shown that when corneal microsomes were incubated with arachidonic acid in the presence of an NADPH-generating system, four metabolites were found. Two of these were biologically active; one of the metabolites, 12(R)-HETE, was found to inhibit partially purified Na.sup.+ /K.sup.+ -ATPase from the corneal epithelium in a dose-dependent manner with an ID.sub.50 of 50 nM. The second compound, 12(R)-hydroxy-5,8,14-eicosatrienoic acid, was found also to be biologically active, leading to vascular reactivity and vasodilation in the intact eye (Schwartzman, M. L., et al. (1987) Invest. Opthalmol. Visual Sci. 3: Suppl. 28, 328). The latter compound is the vasodilator (Murphy, R. C., et al. (1988) J. Biol. Chem. 263: 17197).
U.S. Pat. No. 4,906,467 to Schwartzman, et al. discloses the use of salts or esters of 12(R)-HETE to reduce intraocular pressure in a patient. The compound was found to be particularly useful in treatment of all types of glaucoma. Administering 12(R)-HETE to a patient also is useful in lowering intraocular pressure in preparation for eye surgery, particularly for the removal of cataracts. One of the primary advantages of this compound is that it is normally found in the eye, so side effects of the compound are minimal. Schwartzman, et al. also discloses that the compound 12(R)-HETE causes a decrease in intraocular pressure for a period of several days.
Psoriasis is associated with enhanced synthesis of 12-HETE (Woollard, P. M. (1986) Biochem. Biophys. Res. Commun. 136: 169). 12-HETE is also the major lipoxygenase product of platelets (Hamberg, M. and Samuelsson, B. (1980) Biochem. Biophys. Res. Commun. 95: 1090). Woollard, however, demonstrated that whereas the platelet enzyme produces the 12(S) isomer, that formed by the psoriatic lesions was 12(R)-HETE. This difference in stereochemical configuration endows the 12-HETE with quantitatively different activities.
The compound 12(R)-HETE has been shown to possess potent human neutrophil chemotactic and chemokinetic properties (Dowd, P. M., et al., (1987) J. Invest. Dermatol. 88: 120). The 12(S) isomer is much less potent (Cunningham, F. M. and Woollard P. M. (1987) Prostaglandins 34: 71).
The 5- and 15-lipoxygenase products, leukotriene B.sub.4 (LTB.sub.4) and 15-hydroxyeicosatetraenoic acid (15-HETE), respectively, have been described in keratome specimens of psoriatic skin lesions (Fogh, K., et al., (1987) Arch. Dermatol. Res. 279: 504), and in exudates from abraded psoriatic plaques (Barr, R. M., et al. (1984) Prostaglandins 28: 57. See also, Baer, A. N., et al. (1990) J. Lipid Res. 31: 125.)
In view of the diverse biological activities of the metabolic compounds of arachidonic acids, sufficient amounts of enantiomerically pure compounds are needed for their pre-clinical or clinical uses and for their further biological evaluations. Most of those metabolites of arachidonic acids contain .alpha.-hydroxy-diene subunits or .alpha.,.beta.-dihydroxy-diene subunits.
Isolation of these active metabolites from biological sources is tedious and seldom gives enough quantities for the necessary uses and studies.
Chemical synthesis is an alternate way to obtain enantiomerically pure metabolites of arachidonic acids in larger quantities. Chemical syntheses of 13-hydroxy-9Z, 11E-octadecadienoic acid (13-HODE), and 12-HETE have been reported: Leblanc, Y., et al. (1986) J. Org. Chem. 51: 789, and cited references; Fretland, D. J. and Djuric, S. W. (1989) Leuk. Essent. Fatty Acids 38: 215, and cited references; De Montarby, L., et al. (1989) Bull Soc. Chim. Fr. 419, and cited references; Just, G. and Wang, Z. Y. (1985) Tetrahedron Lett. 26: 2993; Rao, A. V. R., et al. (1985) Tetrahedron Lett. 26: 465; Chan, C., et al. (1988) J. Chem. Soc., Chem. Commun. 971; Nicolaou, K. C. and Abe, R. Y. (1989) Synthesis 898; Taffer, I. M. and Zipkin, R. E. (1987) Tetrahedron Lett. 28: 6543; Corey, E. J., et al. (1978) J. Am. Chem. Soc. 100: 1942; Just, G. and Wang, Z. Y. (1986) J. Org. Chem. 51: 4796; Yadagiri, P., et al. (1986) Tetrahedron Lett. 27: 6039; Mosset, P., et al. (1986) Tetrahedron Lett. 27: 6035; Moustakis, C. A., et al. (1986) Tetrahedron Lett. 27: 303; Corey, E. J., et al. (1980) J. Am. Chem. Soc. 102: 1433; and Djuric, S. W., et al. (1988) Tetrahedron Lett. 29: 3459.
Unfortunately, the reported syntheses for these biologically active metabolites involve multiple synthetic steps. Almost invariably, the total yield from each of these reported syntheses is extremely low. Therefore, there is an urgent need for simple, versatile, concise, and convergent stereocontrolled chemical syntheses of these compounds.